Solid state forms of valbenazine

ABSTRACT

Solid state forms of Valbenazine, Valbenazine salts, processes for preparation thereof and pharmaceutical compositions thereof are disclosed. Processes for the preparation of Valbenazine and intermediates in the preparation thereof are further described.

FIELD OF THE INVENTION

The present disclosure relates to solid state forms of Valbenazine,Valbenazine salts, processes for preparation thereof and pharmaceuticalcompositions thereof. The present disclosure further relates toprocesses for the preparation of Valbenazine and intermediates in thepreparation thereof.

BACKGROUND OF THE INVENTION

Valbenazine has the chemical name(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl L-valinate.

Valbenazine has the following chemical structure:

Valbenazine is being developed by Neurocrine Bioscience for thetreatment of a variety of central nervous system disorders, particularlyinvoluntary hyperkinetic movement disorders such as drug-induced tardivedyskinesia and Tourette's syndrome. In the US, Phase III clinical trialsare on-going for the treatment of drug-induced dyskinesia in patientswith schizophrenia or schizoaffective disorder. Valbenazine is aninhibitor of vesicular monoamine transporter 2 (VMAT2).

Valbenazine is the active ingredient of the approved drug INGREZZA®,indicated for the treatment of adults with tardive dyskinesia. INGREZZAcontains valbenazine, present as valbenazine tosylate salt, with thechemical name, L-Valine,(2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-ylester, 4-methylbenzenesulfonate (1:2).

Valbenazine is disclosed in U.S. Pat. No. 8,039,627.

Valbenazine salts and polymorphs thereof are disclosed in WO2017/075340.

Polymorphism, the occurrence of different crystal forms, is a propertyof some molecules and molecular complexes. A single compound, likeValbenazine, may give rise to a variety of polymorphs having distinctcrystal structures and physical properties like melting point, thermalbehaviors (e.g. measured by thermogravimetric analysis—“TGA”, ordifferential scanning calorimetry—“DSC”), X-ray powder diffraction(XRPD) pattern, infrared absorption fingerprint, Raman absorptionfingerprint, and solid state (¹³C-) NMR spectrum. One or more of thesetechniques may be used to distinguish different polymorphic forms of acompound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, improvingthe dissolution profile, or improving stability (polymorph as well aschemical stability) and shelf-life. These variations in the propertiesof different salts and solid state forms may also provide improvementsto the final dosage form, for instance, if they serve to improvebioavailability. Different salts and solid state forms and solvates ofan active pharmaceutical ingredient may also give rise to a variety ofpolymorphs or crystalline forms, which may in turn provide additionalopportunities to use variations in the properties and characteristics ofa solid active pharmaceutical ingredient for providing an improvedproduct.

Discovering new salts, solid state forms and solvates of apharmaceutical product can provide materials having desirable processingproperties, such as ease of handling, ease of processing, storagestability, and ease of purification or as desirable intermediate crystalforms that facilitate conversion to other salts or polymorphic forms.New salts, polymorphic forms and solvates of a pharmaceutically usefulcompound can also provide an opportunity to improve the performancecharacteristics of a pharmaceutical product (dissolution profile,bioavailability, etc.). It enlarges the repertoire of materials that aformulation scientist has available for formulation optimization, forexample by providing a product with different properties, e.g., adifferent crystal habit, higher crystallinity or polymorphic stabilitywhich may offer better processing or handling characteristics, improveddissolution profile, or improved shelf-life.

For at least these reasons, there is a need for additional solid stateforms (including solvated forms or salts) of Valbenazine.

U.S. Pat. No. 8,039,627 describes a process for Valbenazine, asexemplified in Scheme 1.

The process of U.S. Pat. No. 8,039,627 comprises a chromatographicchiral resolution of Tetrabenazine (Compound 1—(±)-TBZ), which is aracemic mixture of (R,R)- and (S,S)-enantiomers, to obtain the desired(R,R)-enantiomer of tetrabenazine (Compound 2—(+)-TBZ). Compound 2 isthen reduced to (R,R,R)-Dihydrotetrabenazine (Compound 3—(R,R,R)-DHTBZ)and further converted to protected Valbenazine (Compound4—PG-Valbenazine). Compound 4 is deprotected in order to generateValbenazine (Compound 5).

The key intermediate of this process is (R,R,R)-Dihydrotetrabenazine(Compound 3—(R,R,R)-DHTBZ), hence the main challenge of this process isthe chiral resolution of the initial racemic mixture of theTetrabenazine drug (Compound 1—(+)-TBZ).

(R,R,R)-Dihydrotetrabenazine (Compound 3—(R,R,R)-DHTBZ) was found to bethe active ingredient of the already known drug tetrabenazine(Compound 1) and processes for its preparation have been described inthe literature.

WO2012000308, Eur. J. Med. Chem., 2011, 46, 1841-1848 and Med. Chem.Lett., 2010, 46, 105-109 describe a chiral resolution of Tetrabenazineby a formation of diastereomeric salts using (+)-Camphorsulfonic acid.This type of resolution showed very low yields and inconsistent resultswhich makes it difficult to scale up.

WO2008058621 describes a chiral separation of Tetrabenazine using columnchromatography, which is not feasible for scale up and industrialproduction.

WO2008154243, KR1102957, U.S. Pat. No. 8,993,766 and KR1409335 describedifferent asymmetric syntheses for the preparation of(R,R,R)-Dihydrotetrabenazine (Compound 3—(R,R,R)-DHTBZ). These processeseither contain multiple synthetic steps, which ultimately lead to lowyields of the desired compound 3 and/or show poor stereoselectivity.Further, these processes involve exotic and expensive reagents which arenot suitable for scale-up processes.

WO2017112857 (US 20170183346) describes preparation of Valbenazinetosylate by converting Valbenazine HCl to Valbenazine tosylate. Thedescribed process involves reduction of Tetrabenazine (Compound1—(+)(−)TBZ) to racemic Dihydrotetrabenazine, followed by opticalresolution in order to obtain (R,R,R)-Dihydrotetrabenazine (Compound3—(R,R,R)-DHTBZ).

For at least the above reasons, there is a need to have improvedprocesses for preparing Valbenazine, with increased efficiency andreasonable cost that can be used for an industrial scale.

SUMMARY OF THE INVENTION

The present disclosure relates to solid state forms of Valbenazine,processes for preparation thereof, and pharmaceutical compositionscomprising these solid state forms.

The present disclosure also relates to solid state forms of Valbenazinetosylate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms. Valbenazine tosylate asused herein is(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl L-valinate di-tosylate.

The present invention also relates to solid state forms of Valbenazinefumarate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms.

The present disclosure also relates to solid state forms of Valbenazinestearate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms.

The present disclosure also relates to solid state forms of Valbenazinepalmitate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms.

The present disclosure also relates to solid state forms of Valbenazinesulfate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms.

The present disclosure also relates to solid state forms of Valbenazinemesylate, processes for preparation thereof, and pharmaceuticalcompositions comprising these solid state forms.

The present disclosure also provides uses of the solid state forms ofValbenazine or salts thereof for preparing other solid state forms ofValbenazine, Valbenazine salts and solid state forms thereof.

The present disclosure also provides solid state forms of Valbenazine orValbenazine salts of the present disclosure for uses in the preparationof other solid state forms of Valbenazine, Valbenazine salts and solidstate forms thereof.

The present disclosure further provides processes for preparing othersolid state forms of Valbenazine, Valbenazine salts and solid stateforms thereof.

In another embodiment, the present disclosure encompasses the describedsolid state forms of Valbenazine or Valbenazine salts for uses in thepreparation of pharmaceutical compositions and/or formulations,optionally for the treatment of a variety of central nervous systemdisorders, particularly involuntary hyperkinetic movement disorders suchas drug-induced tardive dyskinesia and Tourette's syndrome.Particularly, the described solid state forms of Valbenazine orValbenazine salts may be used in the preparation of pharmaceuticalcompositions and/or formulations for the treatment or prophylaxis of acentral nervous system disorder, a symptom of a neurological disorder,particularly involuntary hyperkinetic movement disorders such as tardivedyskinesia, drug-induced tardive dyskinesia and Tourette's syndrome,Huntington's disease, chorea associated with Huntington's disease,hemiballismus, chorea, senile chorea, tic disorders, tardive dyskinesia,myoclonus, dvstonia and Tourette's syndrome, tremor, dystonia, ballism,tics, akathisia, stereotypies, myoclonus and athetosis, and preferablyfor the treatment or prophylaxis of tardive dyskinesia, drug-inducedtardive dyskinesia and Tourette's syndrome.

In another embodiment, the present disclosure encompasses uses of thedescribed solid state form of Valbenazine or Valbenazine salts for thepreparation of pharmaceutical compositions and/or formulations.

The present disclosure further provides pharmaceutical compositionscomprising the solid state form of Valbenazine or Valbenazine saltsaccording to the present disclosure.

In yet another embodiment, the present disclosure encompassespharmaceutical formulations comprising the described solid state formsof Valbenazine or Valbenazine salts and at least one pharmaceuticallyacceptable excipient.

The present disclosure encompasses processes to prepare saidpharmaceutical formulations of Valbenazine or Valbenazine saltscomprising combining the described solid state form and at least onepharmaceutically acceptable excipient.

The solid state forms defined herein as well as the pharmaceuticalcompositions or formulations of the solid state form of Valbenazine orValbenazine salts can be used as medicaments, particularly for thetreatment of a variety of central nervous system disorders, particularlyinvoluntary hyperkinetic movement disorders such as drug-induced tardivedyskinesia and Tourette's syndrome.

The present disclosure also provides methods of treating of a variety ofcentral nervous system disorders, particularly involuntary hyperkineticmovement disorders such as drug-induced tardive dyskinesia andTourette's syndrome, comprising administering a therapeuticallyeffective amount of the solid state form of Valbenazine or Valbenazinesalt of the present disclosure, or at least one of the herein describedpharmaceutical compositions or formulations, to a subject suffering fromof a central nervous system disorders, particularly involuntaryhyperkinetic movement disorders such as drug-induced tardive dyskinesiaand Tourette's syndrome, or otherwise in need of the treatment.Particularly, the present invention provides methods of treatment orprophylaxis of a central nervous system disorder, a symptom of aneurological disorder, particularly involuntary hyperkinetic movementdisorders such as tardive dyskinesia, drug-induced tardive dyskinesiaand Tourette's syndrome, iuntington's disease, chorea associated withHuntington's disease, herniballismus, chorea, senile chorea, ticdisorders, tardive dyskinesia, myoclonus, dystonia and Tourette'ssyndrome, tremor, dystonia, ballism, tics, akathisia, stereotypies,myoclonus and athetosis, and preferably for the treatment or prophylaxisof tardive dyskinesia, drug-induced tardive dyskinesia and Tourette'ssyndrome.

The present disclosure also provides uses of the solid state forms ofValbenazine or Valbenazine salts of the present disclosure, or at leastone of the above pharmaceutical compositions or formulations for themanufacture of medicaments for treating central nervous systemdisorders, particularly involuntary hyperkinetic movement disorders suchas drug-induced tardive dyskinesia and Tourette's syndrome.

The present disclosure further relates to processes for preparingValbenazine or Valbenazine salts and intermediates in the preparationthereof.

The present disclosure provides an improved procedure for chiralresolution of Tetrabenazine (Compound 1) to obtain the pure(R,R)-enantiomer of Tetrabenazine ((+)-TBZ, Compound 2) using(−)-O,O′-Di-p-Toluoyl-L-Tartaric acid ((−)-DPTTA) as resolving agent.

Also provided is the crystalline form of (+)-Tetrabenazine-(−)-DPTTAsalt((3R,11bR)-3-isobutyl-9,10-dimethoxy-2-oxo-1,2,3,4,5,6,7,11b-octahydropyrido[2,1-a]isoquinolin-5-ium(2S,3 S)-3-carboxy-2,3-bis((4-methylbenzoyl)oxy)propanoate).

In a further aspect, the present disclosure provides a process to obtain(R,R,R)-Dihydrotetrabenazine (Compound 3) by an asymmetric transferhydrogenation (ATH) of a racemic mixture of (R,R)- and(S,S)-Tetrabenazine using a chiral catalyst, for example Ru(II) Noyoricatalysts. In this way, (R,R,R)-Dihydrotetrabenazine (Compound 3) can beobtained using an asymmetric synthesis with only a few synthetic steps.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray powder diffractogram (XRPD) of form L1 ofValbenazine.

FIG. 2 shows an X-ray powder diffractogram (XRPD) of form L2 ofValbenazine.

FIG. 3 shows an X-ray powder diffractogram (XRPD) of form L3 ofValbenazine.

FIG. 4 shows an X-ray powder diffractogram (XRPD) of form L4 ofValbenazine.

FIG. 5 shows an X-ray powder diffractogram (XRPD) of form L2 ofValbenazine.

FIG. 6 shows an X-ray powder diffractogram (XRPD) of form T1 ofValbenazine tosylate.

FIG. 7 shows an X-ray powder diffractogram (XRPD) of form T2 ofValbenazine tosylate.

FIG. 8 shows an X-ray powder diffractogram (XRPD) of form T3 ofValbenazine tosylate.

FIG. 9 shows an X-ray powder diffractogram (XRPD) of form T4 ofValbenazine tosylate.

FIG. 10 shows an X-ray powder diffractogram (XRPD) of form T5 ofValbenazine tosylate.

FIG. 11 shows an X-ray powder diffractogram (XRPD) of form T6 ofValbenazine tosylate.

FIG. 12 shows an X-ray powder diffractogram (XRPD) of form T7 ofValbenazine tosylate.

FIG. 13 shows an X-ray powder diffractogram (XRPD) of form T8 ofValbenazine tosylate.

FIG. 14 shows an X-ray powder diffractogram (XRPD) of form T9 ofValbenazine tosylate.

FIG. 15 shows an X-ray powder diffractogram (XRPD) of form T10 ofValbenazine tosylate.

FIG. 16 shows an X-ray powder diffractogram (XRPD) of form T12 ofValbenazine tosylate.

FIG. 17 shows an X-ray powder diffractogram (XRPD) of form F1 ofValbenazine fumarate.

FIG. 18 shows an X-ray powder diffractogram (XRPD) of form S1 ofValbenazine stearate.

FIG. 19 shows an X-ray powder diffractogram (XRPD) of form P1 ofValbenazine palmitate.

FIG. 20 shows an X-ray powder diffractogram (XRPD) of form HS1 ofValbenazine sulfate.

FIG. 21 shows an X-ray powder diffractogram (XRPD) of form MS1 ofValbenazine mesylate.

FIG. 22 shows an X-ray powder diffractogram (XRPD) of mixture of formT10 and form T12 of Valbenazine tosylate.

FIG. 23 shows a solid state ¹³C-NMR spectrum of form T10 of Valbenazinetosylate (FIG. 23A, 0-200 ppm; FIG. 23B, 100-200 ppm; FIG. 23C, 0-100ppm).

FIG. 24 shows an FT-IR spectrum of form T10 of Valbenazine tosylate.

FIG. 25 shows a solid state ¹³C-NMR spectrum of form T12 of Valbenazinetosylate (FIG. 25A, 0-200 ppm; FIG. 25B, 100-200 ppm; FIG. 25C, 0-100ppm).

FIG. 26 shows an FT-IR spectrum of form T12 of Valbenazine tosylate.

FIG. 27 shows an X-ray powder diffractogram (XRPD) of form I of(+)Tetrabenazine-(−)-DPTTA salt((3R,11bR)-3-isobutyl-9,10-dimethoxy-2-oxo-1,2,3,4,5,6,7,11b-octahydropyrido[2,1-a]isoquinolin-5-ium(2S,3S)-3-carboxy-2,3-bis((4-methylbenzoyl)oxy)propanoate).

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to a solid state form of Valbenazine,processes for preparation thereof and pharmaceutical compositionscomprising this solid state form. The disclosure also relates to theconversion of the described solid state form of Valbenazine to othersolid state forms of Valbenazine, Valbenazine salts and their solidstate forms thereof.

The solid state form of Valbenazine according to the present disclosuremay have advantageous properties selected from at least one of: chemicalor polymorphic purity, flowability, solubility, dissolution rate,bioavailability, morphology or crystal habit, stability—such as chemicalstability as well as thermal and mechanical stability with respect topolymorphic conversion, stability towards dehydration and/or storagestability, a lower degree of hygroscopicity, low content of residualsolvents and advantageous processing and handling characteristics suchas compressibility, or bulk density.

Further, the present disclosure relates to processes for the preparationof Valbenazine or Valbenazine salts and intermediates in the preparationthereof. Particularly, the disclosure relates to the novel compound(+)-Tetrabenazine-(−)-DPTTA salt((3R,11bR)-3-isobutyl-9,10-dimethoxy-2-oxo-1,2,3,4,5,6,7,11b-octahydropyrido[2,1-a]isoquinolin-5-ium(2S,3S)-3-carboxy-2,3-bis((4-methylbenzoyl)oxy)propanoate), describedhereinafter, processes for its preparation and its use as anintermediate in the preparation of Valbenazine or Valbenazine salts, andValbenazine intermediates, such as (R,R,R)-Dihydrotetrabenazine(compound 3). The disclosure further encompasses a process for preparingValbenazine comprising preparing any one or several of the abovecompounds according to the present disclosure and converting it toValbenazine.

Particularly, the disclosure provides improved processes for thepreparation of (R,R,R)-Dihydrotetrabenazine (compound 3), which usesinexpensive and commercially available starting materials. The processesof the present invention consist of simple reaction steps and avoid theuse of expensive reagents and extreme hazardous reaction conditions.Therefore they can be used on an industrial scale.

The following definitions are used throughout this disclosure:

(±)-Tetrabenazine refers to a racemic mixture of (3R,11bR)-Tetrabenazineand (3S,11bS)-Tetrabenazine (compound 1).

(+)-Tetrabenazine refers to (3R,11bR)-Tetrabenazine (compound 2,(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).

(−)-Tetrabenazine refers to (3S,11bS)-Tetrabenazine((3S,11bS)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one).

(−)-DPTTA refers to (−)-O-O′-Di-p-Toluoyl-L-Tartaric acid.

(R,R,R)-Dihydrotetrabenazine refers to (2R,3R,11bR)-Dihydrotetrabenazine(R,R,R)-DHTBZ, compound 3,(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol).

(S,R,R)-Dihydrotetrabenazine refers to (2S,3R,11bR)-Dihydrotetrabenazine(S,R,R)-DHTBZ,(2S,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol)).

A crystal form may be referred to herein as being characterized bygraphical data “as depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which can not necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to factors such asvariations in instrument response and variations in sample concentrationand purity, which are well known to the skilled person. Nonetheless, theskilled person would readily be capable of comparing the graphical datain the Figures herein with graphical data generated for an unknowncrystal form and confirm whether the two sets of graphical data arecharacterizing the same crystal form or two different crystal forms. Acrystal form of Valbenazine referred to herein as being characterized bygraphical data “as depicted in” a Figure will thus be understood toinclude any crystal forms of the Valbenazine, characterized with thegraphical data having such small variations, as are well known to theskilled person, in comparison with the Figure.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or as substantially free of any other solid state(or polymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains about 20% or less, about 10% or less,about 5% or less, about 2% or less, about 1% or less, or 0% of any otherforms of the subject compound as measured, for example, by XRPD. Thus,the solid state form of Valbenazine described herein as substantiallyfree of any other solid state forms would be understood to containgreater than about 80% (w/w), greater than about 90% (w/w), greater thanabout 95% (w/w), greater than about 98% (w/w), greater than about 99%(w/w), or 100% of the subject solid state form of Valbenazine.Accordingly, in some embodiments of the disclosure, the described solidstate forms of Valbenazine may contain from about 1% to about 20% (w/w),from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) ofone or more other solid state forms of the same Valbenazine.

As used herein, unless stated otherwise, XRPD peaks reported herein areoptionally measured using CuK α radiation, X=1.5418 Å.

As used herein, unless stated otherwise, solid state ¹³C NMR chemicalshifts reported herein are preferably measured using a magic anglespinning rate of 11 kHz, and at a temperature of 0° C.

As used herein, the term “isolated” in reference to solid state forms ofValbenazine of the present disclosure corresponds to solid state form ofValbenazine that is physically separated from the reaction mixture inwhich it is formed.

As used herein, Me-THF refers to 2-methyl-tetrahydrofuran, DCM refers todichloromethane, EtOAc refers to ethylacetate and DMF refers todimethylformamide.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature”, often abbreviated “RT.”This means that the temperature of the thing is close to, or the sameas, that of the space, e.g., the room or fume hood, in which the thingis located. Typically, room temperature is from about 20° C. to about30° C., about 22° C. to about 27° C., or about 25° C.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, about 10 to about 18 hours, or about 16 hours.

As used herein, the expression “wet crystalline form” refers to apolymorph that was not dried using any conventional techniques to removeresidual solvent. Examples for such conventional techniques can be, butnot limited to, evaporation, vacuum drying, oven drying, drying undernitrogen flow, etc.

As used herein, the expression “dry crystalline form” refers to apolymorph that was dried using any conventional techniques to removeresidual solvent. Examples of such conventional techniques can be, butare not limited to, evaporation, vacuum drying, oven drying, dryingunder nitrogen flow, etc.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline Valbenazine relates to crystalline Valbenazinewhich does not include any crystalline water (or other solvents) in adefined, stoichiometric amount within the crystal. Moreover, an“anhydrous” form does not contain more than about 1% (w/w) of eitherwater or organic solvents as measured for example by TGA.

The term “solvate”, as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount. The amount of solventemployed in a chemical process, e.g., a reaction or crystallization, maybe referred to herein as a number of “volumes” or “vol” or “V.” Forexample, a material may be referred to as being suspended in 10 volumes(or 10 vol or 10V) of a solvent. In this context, this expression wouldbe understood to mean milliliters of the solvent per gram of thematerial being suspended, such that suspending a 5 grams of a materialin 10 volumes of a solvent means that the solvent is used in an amountof 10 milliliters of the solvent per gram of the material that is beingsuspended or, in this example, 50 mL of the solvent. In another context,the term “v/v” may be used to indicate the number of volumes of asolvent that are added to a liquid mixture based on the volume of thatmixture. For example, adding methyl tert-butyl ether (MTBE) (1.5 v/v) toa 100 ml reaction mixture would indicate that 150 mL of MTBE was added.

As used herein the term non-hygroscopic in relation to crystallineValbenazine refers to less than about 0.2% (w/w) absorption of water atabout 25° C. and about 80% relative humidity (RH) by the crystallineValbenazine as determined for example by TGA. Water can be, for example,atmospheric water.

As used herein, the term “reduced pressure” refers to a pressure ofabout 10 mbar to about 50 mbar.

The present disclosure comprises a crystalline form of Valbenazinedesignated as Form L1. The crystalline Form L1 of Valbenazine can becharacterized by data selected from one or more of the following: anXRPD pattern having peaks at 6.0, 6.8, 13.5, 16.8 and 18.1 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 1; andcombinations of these data. Crystalline Form L1 of Valbenazine may befurther characterized by the XRPD pattern having peaks at 6.0, 6.8,13.5, 16.8 and 18.1 degrees 2-theta±0.2 degrees 2-theta, and also havingone, two, three, four or five additional peaks selected from 12.0, 19.9,20.3, 23.9 and 26.4 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form L1 of Valbenazine may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g. byXRPD pattern having peaks at 6.0, 6.8, 13.5, 16.8 and 18.1 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 1.

The present disclosure further comprises a crystalline form ofValbenazine designated as Form L2. The crystalline Form L2 ofValbenazine can be characterized by data selected from one or more ofthe following: an XRPD pattern having peaks at 4.6, 9.2, 14.8, 18.6 and19.5 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted inFIG. 2 or in FIG. 5; and combinations of these data. Crystalline Form L2of Valbenazine may be further characterized by the XRPD pattern havingpeaks at 4.6, 9.2, 14.8, 18.6 and 19.5 degrees 2-theta±0.2 degrees2-theta, and also having one, two, three, four or five additional peaksselected from 4.2, 7.4, 5.7, 13.8 and 15.7 degrees 2-theta±0.2 degrees2-theta. Alternatively, crystalline Form L2 of Valbenazine may befurther characterized by the XRPD pattern having peaks at 4.6, 9.2,14.8, 18.6 and 19.5 degrees 2-theta±0.2 degrees 2-theta, and also havingone, two, three, four or five additional peaks selected from 10.1, 13.8,17.7, 19.5, 22.3 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form L2 of Valbenazine may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g. byXRPD pattern having peaks at 4.6, 9.2, 14.8, 18.6 and 19.5 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 2.

The present disclosure further comprises a crystalline form ofValbenazine designated as Form L3. The crystalline Form L3 ofValbenazine can be characterized by data selected from one or more ofthe following: an XRPD pattern having peaks at 7.3, 8.0, 14.7, 29.6 and32.5 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted inFIG. 3; and combinations of these data. Crystalline Form L3 ofValbenazine may be further characterized by the XRPD pattern havingpeaks at 7.3, 8.0, 14.7, 29.6 and 32.5 degrees 2-theta±0.2 degrees2-theta, and also having one, two, three, four or five additional peaksselected from 16.1, 19.6, 22.1, 23.4 and 37.3 degrees 2-theta±0.2degrees 2-theta.

Crystalline Form L3 of Valbenazine may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g. byXRPD pattern having peaks at 7.3, 8.0, 14.7, 29.6 and 32.5 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 3.The present disclosure also provides the use of the solid state form ofValbenazine for preparing other solid state forms of Valbenazine,Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine designated as Form L4. The crystalline Form L4 ofValbenazine can be characterized by data selected from one or more ofthe following: an XRPD pattern having peaks at 4.2, 5.7, 8.7 12.6 and25.7 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted inFIG. 4; and combinations of these data. Crystalline Form L4 ofValbenazine may be further characterized by the XRPD pattern havingpeaks at 4.2, 5.7, 8.7 12.6 and 25.7 degrees 2-theta±0.2 degrees2-theta, and also having one, two, three, four or five additional peaksselected from 7.7, 12.3, 15.4, 17.3 and 18.5 degrees 2-theta±0.2 degrees2-theta.

Crystalline Form L4 of Valbenazine may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g. byXRPD pattern having peaks at 4.2, 5.7, 8.7 12.6 and 25.7 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 4.The present disclosure also provides the use of the solid state form ofValbenazine for preparing other solid state forms of Valbenazine,Valbenazine salts and their solid state forms thereof.

The present invention further encompasses Valbenazine ditosylate Me-THFsolvate, Valbenazine ditosylate THF-solvate, and Valbenazine ditosylateisobutanol-solvate.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T1. The crystalline Form T1 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 5.7, 7.0, 7.6,14.2 and 15.2 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 6; and combinations of these data. Crystalline Form T1of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 5.7, 7.0, 7.6, 14.2 and 15.2 degrees 2-theta±0.2 degrees2-theta, and also having one, two, three, four or five additional peaksselected from 15.9, 16.9, 17.8, 18.5 and 22.5 degrees 2-theta±0.2degrees 2-theta.

Crystalline Form T1 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 5.7, 7.0, 7.6, 14.2 and 15.2 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 6.The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T2. The crystalline Form T2 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.2, 15.5, 16.5,17.8, and 19.6 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 7; and combinations of these data. Crystalline Form T2of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.2, 15.5, 16.5, 17.8, and 19.6 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 5.3, 18.3, 22.5, 22.9 and 24.5 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T2 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 6.2, 15.5, 16.5, 17.8, and 19.6 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 7.The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T3. The crystalline Form T3 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.1, 9.0, 14.6,17.3 and 21.6 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 8; and combinations of these data. Crystalline Form T3of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.1, 9.0, 14.6, 17.3 and 21.6 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 10.4, 16.0, 17.8, 20.2 and 21.0 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T3 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 6.1, 9.0, 14.6, 17.3 and 21.6 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 8.The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.Crystalline Form T3 of Valbenazine tosylate may be a solvate.Crystalline Form T3 may be a dioxane solvate. Crystalline Form T3 may bea Me-THF solvate. Crystalline Form T3 may further be characterized by aTGA thermogram showing a mass loss of about 5-7%. Crystalline form T3may contain about 4.5% (w/w) of Me-THF.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T4. The crystalline Form T4 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 5.3, 6.6, 7.8,13.4, and 19.4 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 9; and combinations of these data. Crystalline Form T4of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 5.3, 6.6, 7.8, 13.4, and 19.4 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 10.6, 13.0, 21.4, 23.7, and 24.1 degrees2-theta±0.2 degrees 2-theta, or selected from 10.6, 12.8, 15.8, 21.4 and23.7 degrees 2-theta±0.2 degrees 2-theta

Crystalline Form T4 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 5.3, 6.6, 7.8, 13.4, and 19.4 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 9.The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T5. The crystalline Form T5 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 10.9, 11.4, 16.3,17.4 and 22.3 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 10; and combinations of these data. Crystalline Form T5of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 10.9, 11.4, 16.3, 17.4 and 22.3 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 6.8, 16.9, 17.9, 21.8 and 25.3 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T5 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 10.9, 11.4, 16.3, 17.4 and 22.3degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 10. The present disclosure also provides the use of the solid stateform of Valbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T6. The crystalline Form T6 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.3, 12.3, 13.4,14.0, and 15.5 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 11; and combinations of these data. Crystalline Form T6of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.3, 12.3, 13.4, 14.0, and 15.5 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 16.9, 18.3, 20.6, 21.6, and 24.3 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T6 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 6.3, 12.3, 13.4, 14.0, and 15.5degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 11. The present disclosure also provides the use of the solid stateform of Valbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

Crystalline Form T6 of Valbenazine tosylate may be a solvate.Crystalline Form T6 may be a tetrahydrofuran (THF) solvate. CrystallineForm T6 may further be characterized by a TGA thermogram showing a massloss of about 6-7.5% when heated between 25-250° C.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T7. The crystalline Form T7 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.3, 11.7, 13.1,14.0, and 18.9 degrees 2-theta±0.2 degrees 2-theta an XRPD pattern asdepicted in FIG. 12; and combinations of these data. Crystalline Form T7of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.3, 11.7, 13.1, 14.0, and 18.9 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 12.1, 14.2, 17.4, 18.3, and 19.8 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T7 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 6.3, 11.7, 13.1, 14.0, and 18.9degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 12. The present disclosure also provides the use of the solid stateform of Valbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

Crystalline Form T7 of Valbenazine tosylate may be a solvate.Crystalline Form T7 may be an isobutanol solvate. Crystalline form T7may further be characterized having a TGA showing a mass loss of 7-9%when heated between 25-250° C. Crystalline form T7 may contain about7-8% (w/w) of isobutanol.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T8. The crystalline Form T8 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.2, 11.7, 13.2,14.0, and 18.8 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 13; and combinations of these data. Crystalline Form T8of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.2, 11.7, 13.2, 14.0, and 18.8 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 14.8, 17.4, 18.4, 20.4, and 22.3 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T8 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 6.2, 11.7, 13.2, 14.0, and 18.8degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 13. The present disclosure also provides the use of the solid stateform of Valbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

Crystalline Form T8 of Valbenazine tosylate may be a solvate.Crystalline Form T8 may be a dioxane solvate.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T9. The crystalline Form T9 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.4, 6.9, 8.0,10.4, and 15.5 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 14; and combinations of these data. Crystalline Form T9of Valbenazine tosylate may be further characterized by the XRPD patternhaving peaks at 6.4, 6.9, 8.0, 10.4, and 15.5 degrees 2-theta±0.2degrees 2-theta, and also having one, two, three, four or fiveadditional peaks selected from 13.9, 18.9, 21.0, 22.7, and 25.6 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form T9 of Valbenazine tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by an XRPD pattern having peaks at 6.4, 6.9, 8.0, 10.4, and 15.5 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 14.The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T10. The crystalline Form T10 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.4, 8.0, 10.9,15.9 and 22.4 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 15; and combinations of these data. Crystalline FormT10 of Valbenazine tosylate may alternatively or additionally becharacterized by data selected from one or more of the following: asolid state ¹³C-NMR spectrum with peaks at 168.9, 165.5, 147.2, 106.0and 75.6 ppm±0.2 ppm; or by a solid state ¹³C-NMR spectrum having thefollowing chemical shift absolute differences from a peak at 53.0±1 ppmof 115.9, 112.5, 94.2, 53.0 and 22.6±0.1 ppm; or by a solid state¹³C-NMR spectrum substantially as depicted in FIG. 23; or combinationsof these data.

Crystalline form T10 of Valbenazine tosylate may be furthercharacterized by the XRPD pattern having peaks at 6.4, 8.0, 10.9, 15.9and 22.4 degrees 2-theta±0.2 degrees 2-theta, and also having one, two,three, four or five additional peaks selected from 9.8, 13.6, 14.8,18.7, and 20.5 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form T10 of Valbenazine tosylate may be furthercharacterized by data selected from one of the following: an FT-IRspectrum having one, two, three, four or more peaks selected from 2953,2867, 1747, 1613, 1522, 1465, 1262, 1156, 1118, and 1006 cm⁻¹ 2 cm⁻¹; anFT-IR spectrum as depicted in FIG. 24, and combinations of these data.

Crystalline Form T10 of Valbenazine tosylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. by an XRPD pattern having peaks at 6.4, 8.0, 10.9, 15.9 and 22.4degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 15.

Crystalline Form T10 of Valbenazine tosylate may alternatively oradditionally be characterized by a XRPD pattern having peaks at: 6.4,8.0, 9.8, 10.1, 10.9, 12.7, 13.1, 13.6, 14.8, 15.3, 15.9, 16.3, 17.1,17.6, 18.0, 18.7, 19.5, 20.5, 20.8, 21.7, 22.4, 22.9, 23.4, 23.9, 24.1,24.5, 25.1, 26.1, 26.9, 27.5, 28.4, 29.1, 29.8, 30.2, 30.9, 31.3, 32.0,and 33.0 degrees 2-theta±0.2 degrees 2-theta.

The present disclosure also provides the use of the solid state form ofValbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present disclosure further comprises a crystalline form ofValbenazine tosylate designated as Form T12. The crystalline Form T12 ofValbenazine tosylate can be characterized by data selected from one ormore of the following: an XRPD pattern having peaks at 6.4, 7.6, 12.3,15.2 and 24.9 degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern asdepicted in FIG. 16; and combinations of these data. Crystalline FormT12 of Valbenazine tosylate may alternatively or additionally becharacterized by data selected from one or more of the following: asolid state ¹³C-NMR spectrum with peaks at 166.4, 148.1, 126.9, 109.5and 73.1 ppm±0.2 ppm; or by a solid state ¹³C-NMR spectrum having thefollowing chemical shift absolute differences from a peak at 54.5±1 ppmof 111.9, 93.6, 72.4, 55.0 and 18.6±0.1 ppm; or by a solid state ¹³C-NMRspectrum substantially as depicted in FIG. 25; or combinations of thesedata.

Crystalline Form T12 of Valbenazine tosylate may be furthercharacterized by the XRPD pattern having peaks at 6.4, 7.6, 12.3, 15.2and 24.9 degrees 2-theta±0.2 degrees 2-theta, and also having one, two,three, four or five additional peaks selected from 10.8, 13.9, 15.8,18.9 and 22.3 degrees 2-theta±0.2 degrees 2-theta. Crystalline Form T12of Valbenazine may be further characterized by absence of one, two,three or four peaks selected from 5.3, 5.7, 6.9 and 12.8 degrees2-theta±0.2 degrees 2-theta.

Crystalline form T12 of Valbenazine tosylate may be furthercharacterized by data selected from one of the following: an FT-IRspectrum having one, two, three, four or more peaks selected from 2931,2740, 2663, 2453, 1748, 1606, 1584, 1452, 1227 and 1008 cm⁻¹±2 cm⁻¹; anFT-IR spectrum as depicted in FIG. 26, and combinations of these data.

Crystalline Form T12 of Valbenazine tosylate may alternatively oradditionally be characterized by a XRPD pattern having peaks at: 6.4,7.6, 8.2, 9.7, 10.0, 10.2, 10.8, 11.4, 11.7, 12.3, 13.3, 13.9, 15.2,15.8, 16.5, 16.9, 17.3, 18.0, 18.9, 19.6, 20.0, 20.5, 21.1, 22.3, 23.0,23.8, 24.2, 24.9, 25.6, 26.0, 27.1, 27.5, 28.2, 28.6, 28.9, 29.2, 29.3,30.3, 31.0, 31.2, 31.5, 32.6, 32.8, and 33.2 degrees 2-theta±0.2 degrees2-theta.

Crystalline Form T12 of Valbenazine tosylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. by an XRPD pattern having peaks at 6.4, 7.6, 12.3, 15.2 and 24.9degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 16. The present disclosure also provides the use of the solid stateform of Valbenazine tosylate for preparing other solid state forms ofValbenazine, Valbenazine salts and their solid state forms thereof.

The present invention further encompasses Valbenazine fumarate,Valbenazine stearate, Valbenazine palmitate, Valbenazine sulfate, andValbenazine mesylate.

In one embodiment, the present disclosure further comprises acrystalline form of Valbenazine fumarate designated as Form F1. Thecrystalline Form F1 of Valbenazine fumarate can be characterized by dataselected from one or more of the following: an XRPD pattern having peaksat 4.7, 8.5, 9.5, 11.9 and 15.9 degrees 2-theta±0.2 degrees 2-theta; anXRPD pattern as depicted in FIG. 17; and combinations of these data.Crystalline Form F1 of Valbenazine fumarate may be further characterizedby the XRPD pattern having peaks at 4.7, 8.5, 9.5, 11.9 and 15.9 degrees2-theta±0.2 degrees 2-theta, and also having one, two, three, four orfive additional peaks selected from 14.5, 17.0, 18.5, 19.0 and 19.9degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form F1 of Valbenazine fumarate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 4.7, 8.5, 9.5, 11.9 and 15.9 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 17.

In another embodiment, the present disclosure further comprises acrystalline form of Valbenazine stearate designated as Form S1. Thecrystalline Form S1 of Valbenazine stearate can be characterized by dataselected from one or more of the following: an XRPD pattern having peaksat 4.0, 6.0, 7.3, 10.0 and 14.1 degrees 2-theta±0.2 degrees 2-theta; anXRPD pattern as depicted in FIG. 18; and combinations of these data.Crystalline Form S1 of Valbenazine stearate may be further characterizedby the XRPD pattern having peaks at 4.0, 6.0, 7.3, 10.0 and 14.1 degrees2-theta±0.2 degrees 2-theta, and also having one, two, three, four orfive additional peaks selected from 18.2, 20.2, 29.6, 32.6 and 36.8degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form S1 of Valbenazine stearate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 4.0, 6.0, 7.3, 10.0 and 14.1 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 18.

In yet another embodiment, the present disclosure further comprises acrystalline form of Valbenazine palmitate designated as Form P1. Thecrystalline Form P1 of Valbenazine palmitate can be characterized bydata selected from one or more of the following: an XRPD pattern havingpeaks at 4.5, 6.7, 7.3, 11.3 and 15.8 degrees 2-theta±0.2 degrees2-theta; an XRPD pattern as depicted in FIG. 19; and combinations ofthese data. Crystalline Form P1 of Valbenazine palmitate may be furthercharacterized by the XRPD pattern having peaks at 4.5, 6.7, 7.3, 11.3and 15.8 degrees 2-theta±0.2 degrees 2-theta, and also having one, two,three, four or five additional peaks selected from 20.9, 21.6, 22.6,23.7 and 27.2 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form P1 of Valbenazine palmitate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. by XRPD pattern having peaks at 4.5, 6.7, 7.3, 11.3 and 15.8degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 19.

In a further embodiment, the present disclosure further comprises acrystalline form of Valbenazine sulfate designated as Form HS1. Thecrystalline Form HS1 of Valbenazine sulfate can be characterized by dataselected from one or more of the following: an XRPD pattern having peaksat 6.8, 8.9, 12.6, 15.1 and 21.6 degrees 2-theta 0.2 degrees 2-theta; anXRPD pattern as depicted in FIG. 20; and combinations of these data.Crystalline Form HS1 of Valbenazine sulfate may be further characterizedby the XRPD pattern having peaks at 6.8, 8.9, 12.6, 15.1 and 21.6degrees 2-theta±0.2 degrees 2-theta, and also having one, two, three,four or five additional peaks selected from 17.8, 20.8, 22.9, 20.0 and22.4 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form HS1 of Valbenazine sulfate may be characterized by eachof the above characteristics alone/or by all possible combinations, e.g.by XRPD pattern having peaks at 6.8, 8.9, 12.6, 15.1 and 21.6 degrees2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted in FIG. 20.

In yet a further embodiment, the present disclosure further comprises acrystalline form of Valbenazine mesylate designated as Form MS1. Thecrystalline Form MS1 of Valbenazine mesylate can be characterized bydata selected from one or more of the following: an XRPD pattern havingpeaks at 6.4, 10.3, 11.1, 12.8, and 13.7 degrees 2-theta 0.2 degrees2-theta; an XRPD pattern as depicted in FIG. 21; and combinations ofthese data. Crystalline Form MS1 of Valbenazine mesylate may be furthercharacterized by the XRPD pattern having peaks at 6.4, 10.3, 11.1, 12.8,and 13.7 degrees 2-theta±0.2 degrees 2-theta, and also having one, two,three, four or five additional peaks selected from 15.1, 16.9, 18.8,23.1, and 24.5 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form MS1 of Valbenazine mesylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g. by XRPD pattern having peaks at 6.4, 10.3, 11.1, 12.8, and 13.7degrees 2-theta±0.2 degrees 2-theta and an XRPD pattern as depicted inFIG. 21.

The present disclosure also provides the solid state form of Valbenazineor Valbenazine salt of the present disclosure for use in the preparationof other solid state forms of Valbenazine, Valbenazine salts and theirsolid state forms thereof.

The present disclosure further encompasses processes for preparingValbenazine salt or solid state forms thereof. The process comprisespreparing the solid state forms of the present disclosure, andconverting it to Valbenazine salt. The conversion can be done, forexample, by processes comprising reacting the obtained Valbenazine solidstate form with an appropriate base to obtain the correspondingbase-addition salt.

In another embodiment, the present disclosure encompasses the abovedescribed solid state forms of Valbenazine or Valbenazine salts for usein the preparation of pharmaceutical compositions and/or formulations,optionally for the treatment of central nervous system disorders,particularly involuntary hyperkinetic movement disorders such asdrug-induced tardive dyskinesia and Tourette's syndrome.

In another embodiment, the present disclosure encompasses the use of theabove described solid state forms of Valbenazine or Valbenazine saltsfor the preparation of pharmaceutical compositions and/or formulations.The present disclosure also provides the solid state forms ofValbenazine or Valbenazine salts of the present disclosure for use inthe preparation of pharmaceutical compositions and/or formulations.

The present disclosure further provides pharmaceutical compositionscomprising the solid state form of Valbenazine or Valbenazine saltsaccording to the present disclosure.

In yet another embodiment, the present disclosure encompassespharmaceutical formulations comprising the above described solid stateform of Valbenazine or Valbenazine salts and at least onepharmaceutically acceptable excipient.

The present disclosure encompasses processes to prepare saidformulations of Valbenazine or Valbenazine salts comprising combiningthe above solid state form of Valbenazine or Valbenazine salts and atleast one pharmaceutically acceptable excipient.

The solid state forms of Valbenazine or Valbenazine salts as definedherein, as well as the pharmaceutical compositions or formulationsthereof and at least can be used as medicaments, particularly for thetreatment of central nervous system disorders, particularly involuntaryhyperkinetic movement disorders such as drug-induced tardive dyskinesiaand Tourette's syndrome.

The present disclosure also provides methods of treating central nervoussystem disorders, particularly involuntary hyperkinetic movementdisorders such as drug-induced tardive dyskinesia and Tourette'ssyndrome, comprising administering a therapeutically effective amount ofthe solid state forms of Valbenazine or Valbenazine salts in the presentdisclosure, or at least one of the above pharmaceutical compositions orformulations, to a subject suffering from central nervous systemdisorders, particularly involuntary hyperkinetic movement disorders suchas drug-induced tardive dyskinesia and Tourette's syndrome, or otherwisein need of the treatment.

The present disclosure also provides use of the solid state form ofValbenazine or Valbenazine salts of the present disclosure, or at leastone of the above pharmaceutical compositions or formulations for themanufacture of a medicament for treating central nervous systemdisorders, particularly involuntary hyperkinetic movement disorders suchas drug-induced tardive dyskinesia and Tourette's syndrome.

The present disclosure also provides processes for the preparation ofValbenazine or Valbenazine salts and intermediates in the preparationthereof.

Description of Method A—Chiral resolution of (±)-Tetrabenazine with(−)-DPTTA

The (R,R)- and (S,S)-enantiomers of racemic (±)-Tetrabenazine(Compound 1) can be efficiently separated by using(−)-Di-p-Toluoyl-Tartaric acid ((−)-DPTTA) as a resolving agent.Preferably 0.5-5 equivalents, or 0.6-3 equivalents, or 0.7-2.5equivalents or 0.5-1 equivalent of the resolving agent may be used.Particularly, “equivalents” as used herein refers to, e.g. 0.5-5 molesof DPTTA per mole of racemic (+)-Tetrabenazine. Preferably the chiralresolution is carried out in a ketone or cyclic ketone, alcohol orether, preferably wherein the solvent comprises a ketone, and morepreferably wherein the solvent is acetone. Preferably, the solventcomprises a C₃-C₇-aliphatic ketone (preferably acetone, methyl ethylketone, or methylisobutyl ketone), a C₆₋₁₀ cyclic ketone (preferablycyclohexanone) or a C₁-C₆ alcohol (preferably methanol, ethanol, orisopropanol; or a C₄-C₈ aliphatic or cyclic ether (preferably THF,Me-THF or methyl tert-butyl ether); preferably wherein the solventcomprises a C₃-C₇-aliphatic ketone, and more preferably wherein thesolvent is acetone. In particular, The reaction can be performed inpolar solvents, preferably in ketones, preferably C₃-C₇-aliphaticketones, preferably wherein the ketone is acetone, methyl ethyl ketone,MIBK (methylisobutyl ketone) or in C₆₋₁₀ cyclic ketones, preferablycyclohexanone; or in alcohols, preferably C₁-C₆ alcohols, morepreferably Methanol, Ethanol, or Isopropanol; or in ethers, preferablyC₄-C₈ aliphatic or cyclic ethers, more preferably THF, Me-THF, or MTBE.Particularly preferred solvent is acetone. The solvent can be used in5-20 Volumes (v/wt), or 5-15 Volumes (v/wt), or 5-10 Volumes (v/wt) perweight of racemic (±)-Tetrabenazine. After precipitation, the isolatedproduct is neutralized with an inorganic base such as NH₄OH, K₂CO₃,Na₂CO₃, or NaHCO₃ to obtain the desired (R,R)-enantiomer ofTetrabenazine ((+)-TBZ, Compound 2).

Compound 2 can be reduced by reducing agents, which favor the formationof (R,R,R)-Dihydrotetrabenazine ((R,R,R)-DHTBZ, Compound 3) rather thanthe formation of the (S,R,R)-Diastereomer of Dihydrotetrabenazine.Typical reducing agents which can be used are: NaBH₄, BH₃-complexes(particularly BH₃-THF complex) NaBH(OAc)₃, or LiAlH₄. The reaction canbe conducted in alcoholic solvents, particularly in C₁-C₆ alcohols,preferably Methanol, Ethanol, or Isopropanol, or in ethers, preferablyC₄-C₈ aliphatic or cyclic ethers, more preferably THF, Me-THF, or MTBE,or in other organic solvents such as Ethyl Acetate, or Toluene. Thereaction is preferably performed at a range of temperatures from −30° C.to RT, preferably from −25° C. to +5° C., most preferably from −20° C.to −5° C.

Compound 3 can be reacted with an amine-protected Valine amino acid,i.e.:

wherein PG is an amine protecting group, to obtain protected Valbenazine(PG-Valbenazine, Compound 4) using coupling reagents such as, but notlimited to, DCC (N,N′-dicyclohexylcarbodiimide), EDC(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) or DIC(N,N′-Diisopropylcarbodiimide), preferably with the addition of anappropriate additive such as, but not limited to, NHS(N-hydroxysuccinimide), HOBt (Hydroxybenzotriazole) or DMAP(4-Dimethylaminopyridine). The amino group of valine can be protected byprotecting group PGs such as, but not limited to, Boc(tert-butyloxycarbonyl) or Cbz (carboxybenzyl) protecting groups. Anysuitable protecting groups for amines can be used [e.g. see Greene'sProtective Groups in Organic Synthesis, Fifth Edition (2014), P. G. M.Wuts, Wiley]. The reaction can be conducted in organic solvents such as,but not limited to, Me-THF, DCM, EtOAc or DMF in a range of temperaturesfrom 0° C. to 100° C., preferably from 10° C. to 70° C., most preferablyfrom 20° C. to 30° C.

Amino-protected Valbenazine (Compound 4) can be deprotected to obtainValbenazine (Compound 5). This reaction may be performed using asuitable deprotecting agent in a suitable solvent depending on thenature of the protecting group itself [see Greene's Protective Groups inOrganic Synthesis, Fifth Edition (2014), P. G. M. Wuts, Wiley].Conversion of Compound 3 to Compound 5, or a salt thereof, can beperformed without isolation of Compound 4. A further embodiment of thecurrent invention is (+)-Tetrabenazine-(−)-DPTTA salt((3R,11bR)-3-isobutyl-9,10-dimethoxy-2-oxo-1,2,3,4,5,6,7,11b-octahydropyrido[2,1-a]isoquinolin-5-ium(2S,3S)-3-carboxy-2,3-bis((4-methylbenzoyl)oxy)propanoate). Theinvention further encompasses the use of (+)-Tetrabenazine-(−)-DPTTAsalt or a crystalline form thereof for the preparation of anamino-protected Valbenazine (preferably wherein the amino-protectinggroup is Boc or Cbz), Valbenazine or a salt of Valbenazine, preferablyValbenazine di-tosylate, or for the preparation of (R,R)-Tetrabenazine,or (R,R,R)-Dihydrotetrabenazine.

Particularly, the present disclosure comprises Tetrabenazine-(−)-DPTTAsalt in crystalline form. Preferably the crystalline form of(+)-Tetrabenazine-(−)-DPTTA salt is Form I. The crystalline Form I of(+)-Tetrabenazine-(−)-DPTTA salt can be characterized by data selectedfrom one or more of the following: an XRPD pattern having peaks at 5.7,7.1, 11.3, 17.7 and 19.1 degrees 2-theta±0.2 degrees 2-theta; an XRPDpattern as depicted in FIG. 27; and combinations of these data.Crystalline Form I of (+)-Tetrabenazine-(−)-DPTTA salt may be furthercharacterized by the XRPD pattern having peaks at 5.7, 7.1, 11.3, 17.7and 19.1 degrees 2-theta±0.2 degrees 2-theta, and also having one, two,three, four or five additional peaks selected from 16.5, 17.0, 20.7,22.4 and 23.9 degrees 2-theta±0.2 degrees 2-theta.

The solid state form of (+)-Tetrabenazine-(−)-DPTTA salt according tothe present disclosure may have advantageous properties selected from atleast one of: chemical, enantiomeric/isomeric, or polymorphic purity,flowability, solubility, dissolution rate, bioavailability, morphologyor crystal habit, stability—such as chemical stability as well asthermal and mechanical stability with respect to polymorphic conversion,stability towards dehydration and/or storage stability, a lower degreeof hygroscopicity, low content of residual solvents and advantageousprocessing and handling characteristics such as compressibility, or bulkdensity.

Description of Method B—Asymmetric Transfer Hydrogenation (ATH) ofTetrabenazine

In a further aspect, the present disclosure provides a process to obtain(2R,3R,11bR)-Dihydrotetrabenazine (Compound 3) by an asymmetric transferhydrogenation (ATH) of the racemic mixture of (R,R)- and(S,S)-Tetrabenazine using an ATH chiral metal catalyst such as a chiralRu(II), Rh(II), Ir(II), or Fe(II) catalyst, preferably a Ru(II)-Noyoricatalyst, more preferably a Ru(II)-DPEN catalyst (for exampleRuCl(p-cymene)[(R,R)-Ts-DPEN]).

The asymmetric hydrogenation of racemic Tetrabenazine yields adiastereomeric mixture of (2R,3R,11bR)-Dihydrotetrabenazine (Compound3), originating from the (3R,11bR)-enantiomer of Tetrabenazine, and(2R,3S,11 bS)-Dihydrotetrabenazine, originating from the(3S,11bS)-enantiomer of Tetrabenazine. This diastereomeric mixture canbe further separated to obtain (R,R,R)-Dihydrotetrabenazine, which is amuch easier task than separating a racemic mixture such as (R,R)- and(S,S)-Tetrabenazine (Compound 1) due to the different physicalproperties of a diastereomeric pair in comparison to a racemic pair.This allows separation using conventional methods such ascrystallization or chromatography.

The reaction is preferably conducted using from 0.01-1 mole %,preferably 0.1 to 0.8 mole %, most preferably 0.4-0.6 mole % of ATHchiral catalyst relative to the racemic tetrabenazine starting material.Preferably the chiral catalyst is a Ru(II) asymmetric catalyst,typically a Ru(II)-Cl(arene)(diamine) or Ru(II)Cl₂(PAr₂)₂(diamine)catalyst, in the presence of a hydrogen donor such as H₂, HCO₂H orIsopropanol The reaction also employs a base. In particular the reactionemploys an amine base such as Et₃N (triethylamine), DABCO(1,4-Diazabicyclo[2.2.2]octane), or DBU(1,8-Diazabicyclo(5.4.0)undec-7-ene) or an alkali metal base such asKOH, KO^(t)Bu, or KO^(i)Pr. The reaction is preferably conducted in asuitable solvent. Suitable solvents may be aprotic solvents such as THF,DMF, or DMSO, or aromatic solvents such as Chlorobenzene, Toluene, orBenzene. The reaction is preferably carried out at a temperature between0° C.-100° C., preferably between 20-80° C., most preferably between30-60° C.

Having described the disclosure with reference to certain preferredembodiments, other embodiments will become apparent to one skilled inthe art from consideration of the specification. The disclosure isfurther illustrated by reference to the following examples describing indetail the preparation of the composition and methods of use of thedisclosure. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, may be practiced withoutdeparting from the scope of the disclosure.

Analytical Methods X-Ray Powder Diffraction Method (XRPD):

XRPD analysis was performed on ARL (SCINTAG) powder X-Ray diffractometermodel X'TRA equipped with a solid state detector. Copper radiation of1.5418 Å was used. Scanning parameters: range: 2-40 degrees two-theta;scan mode: continuous scan; step size: 0.05°, and a rate of 3 deg/min.

Prior to analysis, the samples were gently ground using a mortar andpestle to obtain a fine powder. Optionally, silicon powder can be addedin a suitable amount as internal standard in order to calibrate thepositions of the diffractions. The ground sample was adjusted into acavity of the sample holder and the surface of the sample was smoothedusing a cover glass.

Thermogravimetric Analysis (TGA)

Heating between 25-250° C., heating rate: 10° C./min.

Sample weight: 7-15 mg.Crucible: 150 μL alumina crucible.Purging with 40 ml/min N₂ flow.

FT-IR Spectroscopy Thermo FT-IR Spectrometer Nicolet.

The samples were studied in ATR mode.

The spectrum was scanned between 4000-400 cm⁻¹.All the spectra were measured in 16 scans.Resolution: 4.0 cm⁻¹.

¹³C Solid-State NMR Method

¹³C SSNMR was performed at 125 MHz using Bruker Avance II+500 SB probeusing 4 mm rotors

Magic angle was set using KBrHomogeneity of magnetic field checked using adamantaneParameters for Cross polarization optimized using glycineSpectral reference set according to glycine as external standard (176.03ppm for low field carboxyl signal)Scanning parameters:Magic Angle Spinning Rate: 11 kHz; Delay time: 3 sec.; Number of Scans:2048 scans; Temperature: 0° C.

EXAMPLES

Valbenazine starting material can be prepared according to methods knownfrom the literature (for example U.S. Pat. No. 8,039,627).

(±)-Tetrabenazine is the active pharmaceutical ingredient of theapproved drug XENAZINE and is commercially available as a racemicmixture of (3R,11bR)-Tetrabenazine and (3S,11bS)-Tetrabenazine.

P-toluenesulfonic acid was purchased from Sigma Aldrich as monohydratesalt.

Example 1 Preparation of Valbenazine form L1

Valbenazine was charged in glass vial with magnetic stir (36 mg) anddimethylacetamide (20 μL, 1.8 vol). The obtained slurry was heated to70° C. and clear solution was obtained. Water (215 μL, 6 vol) was addedand precipitation was observed. The obtained slurry was stirred for 2hours. The slurry was filtrated and characterized by X-ray powderdiffractogram to give Valbenazine form L1 as depicted in FIG. 1.

Example 2: Preparation of Valbenazine form L2

Valbenazine (66 mg) and a mixture of 9.5:0.5 dichloromethane/methanol(3.2 ml, 48.5 vol) were charged in glass vial. The obtained clearsolution was evaporated to give solid that was dissolved again in9.5:0.5 dichloromethane/methanol (1.6 ml, 24 vol). The solution wasevaporated to give oil that crystallized to give a solid thatcharacterized by X-ray powder diffractogram to give Valbenazine form L2as depicted in FIG. 2.

Example 3: Preparation of Valbenazine form L3

Valbenazine was charged in flask (4 g) and dichloromethane was added(100 ml, 25 vol) clear solution was obtained. After a few minutesprecipitation was observed. The crystals were filtrated andcharacterized by X-ray powder diffractogram to give Valbenazine form L3as depicted in FIG. 3.

Example 4: Preparation of Valbenazine form L4

1 g of Valbenazine was charged in flask. Methanol was added (25 ml, 25vol) and clear solution was obtained. The solution was evaporated. Theobtained solid was characterized by X-ray powder diffractogram to giveValbenazine form L4 as depicted in FIG. 4.

Example 5: Preparation of Valbenazine form L2

Valbenazine (126 mg) was charged in a vial and was heated to 100° C. tomelt. The molten substance, was stored in 100% RH humidity chamber atroom temperature over night to give crystals that were vacuum-dried andcharacterized by X-ray powder diffractogram to give Valbenazine form L2as depicted in FIG. 5.

Example 6: Preparation of Valbenazine Tosylate form T1

Valbenazine (98 mg) was dissolved in methyl ethyl ketone (1 ml).P-toluenesulfonic acid (88 mg, 1.86 eq.) was then added and mixed untilclear solution was obtained. After a few minutes precipitation wasobserved and filtrated. The crystals were vacuum-dried and characterizedby X-ray powder diffractogram to give Valbenazine tosylate form T1.

Example 7: Preparation of Valbenazine Tosylate Form T1

Valbenazine (101 mg) was slurried in water (1 ml). P-toluenesulfonicacid (105 mg, 2.25 eq.) was then added and mixed until clear solutionwas obtained. The solution was stirred overnight precipitation wasobserved and filtrated. The crystals were vacuum-dried and characterizedby X-ray powder diffractogram to give Valbenazine tosylate form T1.

Example 8: Preparation of Valbenazine Tosylate Form T2

Valbenazine (112 mg) was dissolved in 1-propanol (1 ml).P-toluenesulfonic acid (119 mg, 2.2 eq.) was then added and mixed untilclear solution was obtained. The solution was stirred overnight,precipitation was observed and filtration was done. The crystals werevacuum-dried and characterized by X-ray powder diffractogram to giveValbenazine tosylate form T2 as depicted in FIG. 7.

Example 9: Preparation of Valbenazine Tosylate Form T2

Valbenazine (116 mg) was dissolved in Ethanol (1 ml). P-toluenesulfonicacid (114 mg, 2.1 eq.) was then added and mixed until clear solution wasobtained. The solution was stirred overnight, precipitation was observedand filtration was done. The crystals were vacuum-dried andcharacterized by X-ray powder diffractogram to give Valbenazine tosylateform T2.

Example 10: Preparation of Valbenazine Tosylate Form T2

Valbenazine (246 mg) was dissolved in methyl ethyl ketone (2.46 ml).P-toluenesulfonic acid (240 mg, 2.1 eq.) was then added and mixed untilclear solution was obtained. After a few minutes, precipitation wasobserved and filtration was done. The crystals were vacuum-dried andcharacterized by X-ray powder diffractogram to give Valbenazine tosylateform T2.

Example 11: Preparation of Valbenazine Tosylate Form T2

Valbenazine (363 mg) was dissolved in Cyclopentyl methyl ether (3.36ml). P-toluenesulfonic acid (366 mg, 2.1 eq.) was then added and mixeduntil clear solution was obtained. The solution was stirred overnight,precipitation was observed and filtration was done. The crystals werevacuum-dried and characterized by X-ray powder diffractogram to giveValbenazine tosylate form T2.

Example 12: Preparation of Valbenazine Tosylate Form T3

Valbenazine (335 mg) was dissolved in 1,4-dioxane (3.36 ml).P-toluenesulfonic acid (312 mg, 2.0 eq.) was then added and mixed untilclear solution was obtained. The solution was stirred over the weekend,precipitation was observed and filtration was done. The crystals werevacuum-dried and characterized by X-ray powder diffractogram to giveValbenazine tosylate form T3 as depicted in FIG. 8.

Example 13: Preparation of Valbenazine Tosylate Form T3

(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol(10 gr, 0.03 mol, 1 eq) was dissolved in 100 ml of Me-THF (10 V vs.Compound 1 v/w). Then Boc-Val-OH was added (10.21 gr, 0.047 mol, 1.5 eq)followed by the addition of 4-(dimethylamino)pyridine (DMAP) (1.91 gr,0.015 mol, 0.5 eq). Finally,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC-HCl)was added (13.21 gr, 0.068 mol, 2.2 eq) and the reaction mixture wasstirred at RT for 2.5 hours. Upon completion, 100 ml of water was addedto the reaction mixture (10 V vs. Compound 1 v/w). The phases wereseparated. The organic phase was washed with Water (10V). The aqueousphase was removed. Then p-toluenesulfonic acid (PTSA) was added (41.71gr, 0.21 mol, 7 eq). The reaction mixture was stirred at RT for 16hours. Upon completion, the precipitated product was filtered and washedtwice with 10 ml of Me-THF (2×1 V vs. Compound 1 v/w). The obtainedproduct—Valbenazine tosylate was then dried in a vacuum oven at 35° C.for 3 days to obtain 11.33 gr of the desired product (47% yield over twosteps, 99.58% purity). The crystalline form of the product was found tobe form T3 according to XRPD.

Example 14: Preparation of Amorphous Valbenazine Tosylate

Valbenazine tosylate form T2 (3 g) was dissolved in 200 ml ofdichloromethane:methanol (1:1 v/v) mixture. A clear solution wasobtained and the solution was evaporated at vacuum to give amorphousValbenazine tosylate.

Example 15: Preparation of Valbenazine Tosylate Form T3

Amorphous Valbenazine tosylate (50 mg) was suspended in tetrahydrofuran(140 μL, 3 Vol) and stirred at 0° C. overnight. The crystals werevacuum-dried and characterized by X-ray powder diffraction to giveValbenazine tosylate form T3.

Example 16: Preparation of Valbenazine Tosylate Form T3

Amorphous Valbenazine tosylate (50 mg) was suspended in methyl ethylketone (140 μL, 3 Vol) and stirred at 0° C. overnight. The crystals werevacuum-dried and characterized by X-ray powder diffraction to giveValbenazine tosylate form T3.

Example 17: Preparation of Valbenazine Tosylate Form T3

Amorphous Valbenazine tosylate (50 mg) was suspended in 1,4 Dioxane (140μL, 3 Vol) and stirred at 0° C. overnight. The crystals were vacuum- andcharacterized by X-ray powder diffraction to give Valbenazine tosylateform T3.

Example 18: Preparation of Valbenazine Tosylate Form T4

Valbenazine (100 mg) and p-toluenesulfonic acid (118 mg, 2.57 eq.) weremelted at 100° C.; 1.6 ml of water was added to give clear solution. Thesolution was cooled at a rate of 5° C./min; after 1 h there wasprecipitation. The slurry was filtrated and the crystals werevacuum-dried and characterized by X-ray powder diffractogram to giveValbenazine tosylate form T4 as depicted in FIG. 9.

Example 19: Preparation of Valbenazine Tosylate Form T4

A 250 ml reactor was charged with Valbenazine (2.5 g) andp-toluenesulfonic acid (2.87 g, 2.50 eq.) in 20 ml of water. The mixturewas heated to 100° C. to give a clear solution. The solution was cooledto 0° C. during 2 h. The crystals were filtered and characterized byX-ray powder diffractogram to give Valbenazine tosylate form T4.

Example 20: Preparation of Valbenazine Tosylate Form T5

Valbenazine tosylate form T4 (1.5 mg) was dried in a lyophilizer underthe conditions of 50° C. and vacuum of 30 pbar for 27 hours. The samplewas characterized by X-ray powder diffractogram to give Valbenazinetosylate form T5 as depicted in FIG. 10.

Example 21: Preparation of Valbenazine Tosylate Form T6

Valbenazine tosylate form T4 (60 mg) was charged in a vial with amagnetic stirrer. THF (36 vol, 2.1 ml) was added and the obtained slurrywas stirred at room temperature overnight. The slurry was filtrated andcharacterized by X-ray powder diffractogram to give Valbenazine tosylateform T6 as depicted in FIG. 11.

Example 22: Preparation of Valbenazine Tosylate Form T7

Valbenazine tosylate form T3 (96 mg) was charged in a vial with amagnetic stirrer. Isobutanol (10.42 vol, 2.1 ml) was added and theobtained slurry was stirred at room temperature overnight. The slurrywas filtrated and characterized by X-ray powder diffractogram to giveValbenazine tosylate form T7 as depicted in FIG. 12.

Example 23: Preparation of Valbenazine Tosylate Form T8

Amorphous Valbenazine tosylate (202 mg) was charged in a vial with amagnetic stirrer. 1,4 Dioxane (3 vol, 0.8 ml) was added and the obtainedslurry was stirred at 0° C. for 3 h. The slurry was filtrated andcharacterized by X-ray powder diffraction to give Valbenazine tosylateform T8 as depicted in FIG. 13.

Example 24: Preparation of Valbenazine Tosylate Form T9

Valbenazine tosylate form T6 (2 gr) was dried without freezing in alyophilizer at between 30° C. to 50° C. and less than 100 pbar for 55hours. The product was characterized by X-ray powder to give Valbenazinetosylate form T9 as depicted in FIG. 14.

Example 25: Preparation of Valbenazine Tosylate Form T10

Valbenazine tosylate form T9 as prepared according to example 24 wasleft in a vial for 3 days at RT without stirring to give a mixture ofT9+T10 the mixture was dried without freezing in a lyophilizer at 50° C.and less than 100 pbar, total time of drying was 22 h. The product wascharacterized by X-ray powder to give Valbenazine tosylate form T10 asdepicted FIG. 15.

Example 26: Preparation of Valbenazine Tosylate Form T10

Valbenazine tosylate form T6 (THF solvate, 0.2 gr) was heated in avacuum oven for 1 hour, at about 70° C. The solid was tested by XRD, andfound to be Valbenazine tosylate Form T10.

Example 27: Preparation of Valbenazine Tosylate Form T12

(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2Hpyrido[2,1-a]isoquinolin-2-ol (43.6 gr, 136 mmol) was slurried in 1 Vol.di-chloromethane (DCM, 43.6 mL) and charged into a 1 L reactor.4-(dimethylamino)-pyridine (DMAP, 8.3 g, 68 mmol), Boc-Val-OH (44.5 gr,204 mmol) and 5 Vol. (218 mL) of DCM were added to the reactor andstirred for 5 min at room temperature. ThenN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide HCl (EDC HCl, 57.6 gr,300 mmol) was added to the reaction mixture followed by addition of 1Vol (43.6 mL) of DCM. The mixture was stirred for 3 hours at roomtemperature. After completion of reaction, the reaction mixture waswashed with water (10 Vol.) followed by phase separation. Additionalwashing with water (10 vol) was carried out and after phase separationp-Toluenesulfonic acid monohydrate (104 g, 544 mmol) was added to theorganic phase and stirred for 19 hours at 35° C. 87 ml of the obtainedsolution was diluted with additional DCM (13 ml) and MeOH (100 ml). Thesolvents were evaporated to obtain an oil. THF (100 ml) was then addedto the oil and evaporated. The obtained oil was dissolved in THF:MeOH(98:2, 5.6 vol) and the solution was cooled to −5° C. The solution wasthen seeded with Valbenazine tosylate form T6 and stirred for 18 hoursat −5° C. The precipitate was collected by vacuum filtration and driedin a vacuum oven at 70° C. (less than 50 mbar) for 72 hours. The hotsolid was taken out from the oven directly to room temperature undernitrogen environment to produce Valbenazine tosylate form T12. Form T12was characterized by X-ray powder and its diffractogram is presented inFIG. 16.

Example 28: Preparation of Seeding Crystals Valbenazine Tosylate Form T6

Amorphous form of Valbenazine tosylate (241 mg) was slurried in THF/MeOH(0.2% MeOH, 5.01 ml, 20 vol) at 0° C. for 24 hours. The product wasisolated by vacuum filtration to afford Valbenazine tosylate Form T6.

Example 29: Preparation of Valbenazine Tosylate Mixture of Form T10 andForm T12

Valbenazine tosylate form T10 (100 mg) was heated to 100° C. in an ovenfor 1 hour. The hot solid was taken out from the oven directly to asealed vial at room temperature for 24 hrs. The solid was characterizedby X-ray powder diffractogram to give a mixture of valbenazine tosylateform T10 and form T12. The diffractogram is presented in FIG. 22.

Example 30: Preparation of Valbenazine Tosylate Form T10

501 mg of amorphous valbenazine tosylate was slurried in 5 mL (10 Vol.)of iso-butanol, cooled to 0° C. and stirred overnight. The slurry wasfiltered, the resulting solid was dried under vacuum at 70° C.overnight. The white powder was further dried under vacuum at 100° C.overnight to afford Valbenazine tosylate form T10.

Example 31: Preparation of Valbenazine Tosylate Form T10

501 mg of amorphous valbenazine tosylate was slurried in 5 ml (10 Vol.)of dioxane, cooled to 0° C. and stirred over 48 h. The slurry wasfiltered and dried under vacuum at 70° C. overnight to affordValbenazine tosylate form T10.

Example 32: Preparation of Valbenazine Tosylate Form T7

(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2Hpyrido[2,1-a]isoquinolin-2-ol (21.8 gr, 68 mmol) was dissolved in 1 Vol.(21.8 mL) DCM and charged into the reactor. DMAP (4.15 gr, 34 mmol),Boc-Val-OH (22 gr, 102 mmol) and 7 Vol. (152.6 mL) DCM were added. Themixture was stirred at RT until complete dissolution. EDC HCl (28.8 gr,150 mmol) in 2 Vol. of DCM was added. The mixture was stirred over 3hours at 25° C. followed by washings with H₂O (10 Vol.×2).p-Toluenesulfonic acid monohydrate (52 gr, 272 mmol) was added to thewashed mixture and stirred overnight at 35° C. Iso-butanol 5 Vol. (109mL) was added and followed by distillation at 35° C. (under vacuumconditions) to 5 Vol. of the mixture. The mixture was cooled to 15° C.,followed by seeding with 1% (w/w) of form T7 of Valbenazine tosylate andcooling to 5° C. over 1 h. After cooling, 2 Vol. (44 mL) of isobutanolwere added followed by stirring overnight. The precipitate was filteredand washed with 2 Vol. (21.8 mL) of isobutanol. A white powder wasobtained (73.55% yield) to afford Valbenazine tosylate form T7.

Example 33: Preparation of Valbenazine Fumarate Form F1

A flask was charged with Valbenazine (500 mg) and acetone (2.5 ml, 5vol) and stirred at RT until a clear solution was obtained. Fumaric acid(278 mg, 2 eq.) was added and the mixture was stirred overnight at RT. Athick precipitation was obtained and another 5 ml of acetone were added.The slurry was filtered and the residue characterized by X-ray powderdiffractogram to give Valbenazine fumarate Form F1 as depicted in FIG.17.

Example 34: Preparation of Valbenazine Stearate Form S1

A flask was charged with Valbenazine (500 mg) and2-Methyltetrahydrofuran (Me-THF) (2.5 ml, 5 vol) and stirred at RT untila clear solution was obtained. Stearic acid (856 mg, 2.5 eq.) was addedand the mixture was stirred overnight at RT. The flask was transferredto an ice bath and the solution was cooled for 15 min with stirring togive a precipitation. The crystals were filtered and characterized byX-ray powder diffractogram to give Valbenazine stearate Form S1 asdepicted in FIG. 18.

Example 35: Preparation of Valbenazine Palmitate Form P1

A flask was charged with Valbenazine (50 mg) and Acetone (500 μL, 5 vol)and stirred at RT until a clear solution was obtained. Palmitic acid(153 mg, 2.5 eq.) was added and the mixture was stirred overnight. Thecrystals were filtered and characterized by X-ray powder diffractogramto give Valbenazine palmitate Form P1 as depicted in FIG. 19.

Example 36: Preparation of Valbenazine Sulfate Form HS1

A flask was charged with Valbenazine (50 mg) and n-butanol (500 μL, 5vol) and stirred at RT until a clear solution was obtained. Sulfuricacid (16 μL, 2.5 eq.) was added and the mixture was stirred for 3 h atRT. The crystals were filtered and characterized by X-ray powderdiffractogram to give Valbenazine sulfate Form HS1 as depicted in FIG.20.

Example 37: Preparation of Valbenazine Mesylate Form MS1

To a stirred solution of Valbenazine base (2 g, 1 eq) in a mixture ofIsopropanol (20 ml, 10 vol) and diethyl ether (6.5 ml, 3.25 vol),methanesulfonic acid (651 μL, 2.10 eq) was added and clear solution wasobtained. The solution was stirred at RT for 30 minutes. The solutionwas cooled in an ice bath for 2 h and an oil was obtained. The mixturewas stirred at RT overnight. The solid was filtered under nitrogen,washed with 4 ml diethyl ether and dried in a vacuum oven at 50° C.overnight to give Valbenazine mesylate Form MS1. The product wascharacterized by XRPD as depicted in FIG. 21.

Example 38: Chiral Resolution of Tetrabenazine with (−)-DPTTA (Method A)

(±)-Tetrabenazine (Compound 1, 200 gr, 0.62 mol, 1 eq) was dissolved in2 L of Acetone (10 V vs. Tetrabenazine v/wt) in a 3 L glass reactor.Then (−)-O,O′-Di-p-toluoyl-L-tartaric acid ((−)-DPTTA) was added (243.6gr, 0.62 mol, 1 eq). The reaction mixture was stirred at RT for 16 h.The precipitated product was filtrated and washed with Acetone (2×0.5 Vvs. Tetrabenazine v/wt). The mother liquor after precipitation wasdistilled off. The obtained residue was dissolved in 1 L of Acetone (5 Vvs. Tetrabenazine v/wt) in a 3 L reactor, heated to 60° C. and stirredfor 2 hours. The solution was then cooled to RT and stirred for 16 h.The precipitated product was filtrated and washed with Acetone (2×0.5 Vvs. Tetrabenazine v/wt). The precipitatedproduct—(+)-Tetrabenazine-(−)-DPTTA salt from both steps was combinedand dissolved in EtOH (6 V vs. (+)Tetrabenazine-(−)-DPTTA salt v/wt) ina 3 L glass reactor and cooled to 0° C. The pH was adjusted to pH=8-8.5with NH₄OH. Water (10V vs. (+)-Tetrabenazine-(−)-DPTTA salt v/wt) wasadded dropwise and the reaction mixture was stirred at 0° C. for 1 h.The precipitated product was filtrated and washed with water (2 V, vs.(+)-Tetrabenazine-(−)-DPTTA salt v/wt) to obtain the desired(+)-Tetrabenazine (R,R) enantiomer (Compound 2, 134 gr, 67% overallyield, 97-98% chiral purity).

Example 39: Asymmetric Transfer Hydrogenation of (±)-Tetrabenazine(Method B)

(±)-Tetrabenazine (Compound 1, 3 gr, 0.0095 mol, 1 eq) was dissolved in18 ml of Toluene (6 V vs. Tetrabenazine v/wt) in a 100 ml round-bottomflask under Nitrogen atmosphere. RuCl(p-cymene)[(R,R)-Ts-DPEN] was added(0.03 gr, 0.0005 mol, 0.005 eq), followed by the addition of 5:2HCO₂H:Et₃N complex (4.37 ml, 0.05 mol, 5.4 eq). The reaction mixture washeated to 50° C. and stirred for 16 h. Upon completion, the reactionmixture was diluted with 50 ml of water and 50 ml of Ethyl Acetate. Thelayers were separated and the organic layer was washed with 50 ml ofwater. The organic layer was then dried with Na₂SO₄, filtered and thesolvent was removed under reduced pressure to obtain(R,R,R)-Dihydrotetrabenazine (Compound 3) and itsdiastereomer—(R,S,S)-Dihydrotetrabenazine as a 1:1 mixture.

Example 40: Preparation of (+)-Tetrabenazine((3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,1b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one)A:(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one,(−)-Di-p-toluoyl-L-tartrate

(−)-Di-p-toluoyl-L-tartaric acid (730.3 g, 1.89 mole),3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one(600 g, 1.89 mole) and Acetone (6000 ml, 10 vol) were charged in toreactor vessel at −10° C. The obtained solution was stirred at −5° C.till precipitations were obtained. The reaction mixture was then heatedto 25° C. and stirred for 10 hours. The slurry was heated to reflux andstirred for 2 hours at reflux temperature. The obtained slurry wascooled to 25° C. and stirred for additional 12 hours. The product wasisolated by vacuum filtration, washed with Acetone and dried in vacuumoven at 40° C. to obtain(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one,(−)-Di-p-toluoyl-L-tartarate (771 g, 93.3% chiral purity; 58% yield).

Mother liquor from the previous step was loaded to the reactor vessel;the volume of the solution was reduced by distillation to total volumeof 2 liters. The solution was seeded with(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one,(−)-Di-p-toluoyl-L-tartarate (0.44 gr) at 25° C. and stirred for 5hours. The obtained slurry was heated to 62° C., stirred for 2 hoursthen cooled to 25° C. for 2 hours and stirred at that temperature for 18hours. The product was isolated by vacuum filtration washed with Acetone(2*0.5 vol) and dried in vacuum oven at 40° C. for 16 hours to obtain(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one,(−)-Di-p-toluoyl-L-tartarate (265 g, 20% yield).

B:(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one

(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one,(−)-Di-p-toluoyl-L-tartarate (1031 g, 1.466 mole), Ethanol (6186 ml, 6vol) and water (1031 ml, 1 vol) were charged to reactor vessel, cooledto 0° C. then NaHCO₃ (309.3 g, 3.66 mole) and additional amount of water(3093 ml, 3 vol) were added to the reaction mixture and stirred for 2hour. Additional water (6186 ml, 6 vol) was added dropwise and stirredfor 15 hours. The product(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-onewas isolated by vacuum filtration, washed with water and dried in vacuumoven (422 g, 90.75% yield, 98.42% chiral purity).

Example 41: Preparation of (R,R,R)-DHTBZ((2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol)

(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one(376 g, 0.945 mole) and THF (3760 ml, 10 vol), were loaded to thereactor and cooled to −15° C. BH3*THF 1 M solution (1743.6 ml, 1.74 eq)was added dropwise during 5.5 hours. The reaction mixture was stirredfor 2 hours and the reaction completion was monitored by HPLC. Ammoniumhydroxide solution (25%, 4512 ml, 12 vol) was added dropwise during 3hours. The solution was heated to 35° C. and stirred for 12 hours. Thesolution was cooled to 25° C., NaCl sat. Solution (1880 ml, 5 vol) andMTBE (1880 ml, 5 vol) were added. The organic phase was evaporated toreduce the volume to 400-450 ml and then EtOH (1880 ml, 5 vol) wasadded. The product was precipitated by dropwise addition of water (3760ml, 10 vol) during 1.5 hours and stirred for 16 hours. The product wascollected by vacuum filtration, washed with EtOH/Water 1:4 (940 ml, 2.5vol) and dried in vacuum oven at 35° C. for 48 hours to obtain (302 g,80.4% yield, 96.3% purity).

1-44. (canceled)
 45. Solid state form of Valbenazine sulfate designatedas Form HS1, characterized by data selected from one or more of thefollowing: (a) a XRPD pattern having peaks at 6.8, 8.9, 12.6, 15.1 and21.6 degrees 2-theta 0.2 degrees 2-theta; (b) a XRPD pattern as depictedin FIG. 20; (c) or combinations of these data.
 46. The solid state formof Valbenazine sulfate according to claim 45, characterized by a XRPDpattern having peaks at 6.8, 8.9, 12.6, 15.1 and 21.6 degrees2-theta±0.2 degrees 2-theta, and also having one, two, three, four orfive additional peaks selected from 17.8, 20.8, 22.9, 20.0 and 22.4degrees 2-theta±0.2 degrees 2-theta.
 47. A process for preparing apharmaceutical composition and/or formulation comprising combining thesolid state form of Valbenazine sulfate according to claim 45 with atleast one pharmaceutically acceptable excipient.
 48. A pharmaceuticalcomposition or formulation comprising the solid state form ofValbenazine sulfate according to claim
 45. 49. A pharmaceuticalcomposition or formulation according to claim 48 comprising at least onepharmaceutically acceptable excipient, wherein the pharmaceuticalcomposition or formulation is for oral administration.